Journal of Huntington's Disease

Our physiology and behavior follow precise daily programs that adapt us to the alternating opportunities and challenges of day and night. Under experimental isolation, these rhythms persist with a period of approximately one day (circadian), demonstrating their control by an internal autonomous clock. Circadian time is created at the cellular level by a transcriptional/translational feedback loop (TTFL) in which the protein products of the Period and Cryptochrome genes inhibit their own transcription. Because the accumulation of protein is slow and delayed, the system oscillates spontaneously with a period of ∼24 hours. This cell-autonomous TTFL controls cycles of gene expression in all major tissues and these cycles underpin our daily metabolic programs. In turn, our innumerable cellular clocks are coordinated by a central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. When isolated in slice culture, the SCN TTFL and its dependent cycles of neural activity persist indefinitely, operating as “a clock in a dish”. In vivo, SCN time is synchronized to solar time by direct innervation from specialized retinal photoreceptors. In turn, the precise circadian cycle of action potential firing signals SCN-generated time to hypothalamic and brain stem targets, which co-ordinate downstream autonomic, endocrine, and behavioral (feeding) cues to synchronize and sustain the distributed cellular clock network. Circadian time therefore pervades every level of biological organization, from molecules to society. Understanding its mechanisms offers important opportunities to mitigate the consequences of circadian disruption, so prevalent in modern societies, that arise from shiftwork, aging, and neurodegenerative diseases, not least Huntington’s disease.

Sleep occupies a peculiar place in our lives and in science, being both eminently familiar and profoundly enigmatic. Historically, philosophers, scientists and artists questioned the meaning and purpose of sleep. If Shakespeare’s verses from MacBeth depicting “Sleep that soothes away all our worries” and “relieves the weary laborer and heals hurt minds” perfectly epitomize the alleviating benefits of sleep, it is only during the last two decades that the growing understanding of the sophisticated sleep regulatory mechanisms allows us to glimpse putative biological functions of sleep. Sleep control brings into play various brain-wide processes occurring at the molecular, cellular, circuit, and system levels, some of them overlapping with a number of disease-signaling pathways. Pathogenic processes, including mood disorders (e.g., major depression) and neurodegenerative illnesses such Huntington’s or Alzheimer’s diseases, can therefore affect sleep-modulating networks which disrupt the sleep-wake architecture, whereas sleep disturbances may also trigger various brain disorders. In this review, we describe the mechanisms underlying sleep regulation and the main hypotheses drawn about its functions. Comprehending sleep physiological orchestration and functions could ultimately help deliver better treatments for people living with neurodegenerative diseases.

Sleep and circadian alterations are common in patients with Huntington’s disease (HD). Understanding the pathophysiology of these alterations and their association with disease progression and morbidity can guide HD management. We provide a narrative review of the clinical and basic-science studies centered on sleep and circadian function on HD. Sleep/wake disturbances among HD patients share many similarities with other neurodegenerative diseases. Overall, HD patients and animal models of the disease present with sleep changes early in the clinical course of the disease, including difficulties with sleep initiation and maintenance leading to decreased sleep efficiency, and progressive deterioration of normal sleep architecture. Despite this, sleep alterations remain frequently under-reported by patients and under-recognized by health professionals. The degree of sleep and circadian alterations has not consistently shown to be CAG dose-dependent. Evidence based treatment recommendations are insufficient due to lack of well-designed intervention trials. Approaches aimed at improving circadian entrainment, such as including light therapy, and time-restricted feeding have demonstrated a potential to delay symptom progression in some basic HD investigations. Larger study cohorts, comprehensive assessment of sleep and circadian function, and reproducibility of findings are needed in future in order to better understand sleep and circadian function in HD and to develop effective treatments.

Sleep and circadian disruption affects most individuals with Huntington’s disease (HD) at some stage in their lives. Sleep and circadian dysregulation are also present in many mouse and the sheep models of HD. Here I review evidence for sleep and/or circadian dysfunction in HD transgenic animal models and discuss two key questions: 1) How relevant are such findings to people with HD, and 2) Whether or not therapeutic interventions that ameliorate deficits in animal models of HD might translate to meaningful therapies for people with HD.

Sleep dysfunction is highly prevalent in Huntington’s disease (HD). Increasing evidence suggests that such dysfunction not only impairs quality of life and exacerbates symptoms but may even accelerate the underlying disease process. Despite this, current HD treatment approaches neither consider the impact of commonly used medications on sleep, nor directly tackle sleep dysfunction. In this review, we discuss approaches to these two areas, evaluating not only literature from clinical studies in HD, but also that from parallel neurodegenerative conditions and preclinical models of HD. We conclude by summarizing a hierarchical framework of current medications with regard to their impact on sleep, and by outlining key emerging sleep therapies.

Sleep disorders are common in Huntington’s disease (HD) but are complex; their bi-directional associations with psychiatric, cognitive, and motor dysfunction makes them especially important to both consider and to treat. The author provides a perspective in brief regarding sleep disturbances in HD, based on her experience caring for, and learning from, patients with HD for more than twenty years.

In this edition of the Huntington’s Disease Clinical Trials Corner, we expand on the GENERATION HD2 (tominersen) and on the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001. We also comment on the recent findings from the PROOF-HD trial, and list all currently registered and ongoing clinical trials in Huntington’s disease.